Neuro (Test 2) - Lect 11 & 12 - Affective Disorders

Front 1

Explain the monoamine hypothesis of depression

Back 1

deficiency in the amount of or function of cortical and limbic serotonin, norepinephrine, and dopamine contributes to depression.

**Could be due to homozygous serotonin transporter gene polymorphism

Front 2

According to the monoamine hypothesis, depleting pts of what will cause a relapse of depression if the pt responds to serotnergic or noradrenergic antidepressants?

Back 2

removing Tryptophan and catecholamines

Front 3

All Available anti-depressants effect the monoamine system, enhancing the synaptic availability of what?

Back 3

Serotonin, NE, or Dopamine.

**this is done via Inc BDNF

Front 4

Will a depressed pt with elevated cortisol levels respond to an Dexamethasone ACTH suppression test?

Back 4

NO, they have chronically elevated CTRH which keeps ACTH high.

**this elevated cortisol causes mood symptoms and cognitive deficits.

Front 5

Glucocorticoid receptors are found in high concentration in the ________ and when cortisol binds, there is a decrease in ____ synthesis

Back 5

Hippocampus, BDNF.

**remember: activation of monoamine rec by antidepressants INC BDNF transcription and downregulate the hyperactive HPA axis

Front 6

List the different classes of Anti-depressants

Back 6

1.Selective Serotonin reuptake inhibitors (SSRIs).

2.Serotonin-NE Reuptake Inhibitors (SNRIs).

3.TCAs.

4.Serotonin Antagonists.

5.Monoamine Oxidase Inhibitors.

6.Tetra/Unicyclic Antidepressants.

Front 7

MOA of SSRIs

Back 7

Inhibition of the Serotonin transporter (SERT) located on both pre and post synaptic neurons.

**Dont affect any other receptors

Front 8

List the SSRIs

Back 8

1.Flouxetine**.

2.Sertraline.

3.Citalopram.

4.Paroxetine.

5.Fluvoxamine.

6.Escitalopram.

Front 9

All SSRIs have long half lives, why must a pt be off Flouxetine for > 4weeks before you can give them a MAOI?

Back 9

Still a risk of Serotonin Syndrome since the Active Metabolite is Norfluoxetine which has a 1/2 life of 180hrs.

Front 10

Which 2 SSRIs cause DISCONTINUATION Syndrome cahracterized by dizziness and paresthesias 1-2 days after stoping the medication? which of these also causes wgt loss?

Back 10

1.Paroxetine (causes both).

2.Sertraline.

**Due to their shorter 1/2 life

Front 11

What is major pt complaint on SSRIs?

Back 11

Dec sexual function and interest

Front 12

Which 2 SSRIs are POTENT CYP2D6 inhibitors requiring you to monitor dosing of other drugs metabolized by CYP2D6 (ex: SNRIs, TCAs)

Back 12

1.Paroxetine.

2.Fluoxetine

Front 13

MOA of SNRIs

Back 13

Bind and inhibit both SERT and NET

Front 14

List the 3 SNRIs

Back 14

1.Duloxetine (also used for pain).

2.Milnacipran.

3.Venlafaxine.

Front 15

Which SNRI can also be used for Fibromyalgia (which has a strong depression component)

Back 15

Milnacipran

Front 16

which has a longer 1/2 life, SSRIs or SNRIs (think about for dosing purposes, X/day)? which has more CYP interactions?

Back 16

SSRIs

Front 17

Since SNRIs also block the reuptake of NE, the cause Inc Noradrenergic SEs like HTN, Inc HR, and Insomnia/agitation (CNS stimulation). Which SNRI is the most cardiotoxic?

Back 17

Venlafaxine

Front 18

When would you consider using Tricyclic Antidepressants to treat depression? what time of day would you give them?

Back 18

If SSRIs or SNRIs did NOT work.

**Given at night due to sedation

Front 19

List 3 TCADs and their additional use besides depression

Back 19

1.Imipramine: Enuresis.

2.Amitripyline: Post-herpetic Neuralgia, Diabetic neuropathic pain.

3.Clomipramine: OCD.

Front 20

TCADs target every receptor type, what are some Key SEs b/c of this

Back 20

1.Anti-ACh: Dry mouth, constipation.

2.Anti-H: sedation.

3.Anti-adrenergic: orthostatic HTN.

4.Dec sex drive

Front 21

Is the Discontinuation syndrome of TCADs the same as with SNRIs and SSRIs? (dizziness and paresthesia)?

Back 21

NOO, Prominent CHOLINERGIC REBOUND and flu like symptoms

Front 22

List the 2 Serotonin Antagonists

Back 22

1.Trazodone.

2.Nefazodone.

Front 23

MOA of Trazadone

Back 23

Block 5-HT(2A) receptor.

**Same as LSD

Front 24

Trazadone is BLACK BOXED for what?

Back 24

Hepatotoxicity

Front 25

MAO(A) will increase what NTs in the neuron? MAO (B) will increase what NTs in the neuron?

Back 25

A:

1.Dopamine.

2.NE.



B:

1.Serotonin.

2.Histamine

Front 26

What is ths only MAO Inhbitor used for depression which is an irreversible, nonselective MAO Inhibitor

Back 26

Phenelzine

Front 27

SEs of Phenelzine

Back 27

1.Orthostatic Hypotension.

2.Wgt gain.

3.Dec Sex drive.

4.Inc sedation.

5.Confusion.

Front 28

Describe the discontinuation syndrome from MAO inhibitors

Back 28

Delirium-like: psychosis, excitement, confusion.

Front 29

Phenelzine and MAOIs will cause Serotonin Syndrome (Coma, HTN, Tachycardia, and myoclonus, and tremor) with which Anti-depressant drug classes

Back 29

1.SSRIs.

2.SNRIs.

3.TCADs.

4.Meperidine.

**All need to be discontinued 2 weeks prior to MAOI use,

Fluoxetine needs to be 4-5 weeks prior.

Front 30

MAOI (Phenelzine) inhibit the breakdown of _____ in the GI tract which leads to ______ ___ and __. What foods should be avoided?

Back 30

Tyramine,

Elevated BP & MI.


**Foods that contain Tyramine:

1.Aged Cheese.

2.Tap beer.

3.Soy.

Front 31

What SE should you be worried about in your pt taking Phenelzine that also does METH?

Back 31

HTN

Front 32

Which 2 drugs might you switch your pt to if they complained about sexual SEs?

Back 32

1.Bupropion.

2.Mirtazapine (a2 Antagonist on presynaptic terminal)

Front 33

What is Unique about the Bupropion elmination?

Back 33

it is BIPHASIC:

1st: lasts 1 hr.

2nd: lasts 14hrs.

Front 34

Which unclassified antidepressant can cause parkinson syndrome?

Back 34

Amoxapine: (has D2 blocking activity

Front 35

1st line Depression

Back 35

SSRIs.

**Also SNRIs, Bupropion, Mirtazapine

Front 36

What drug is also used to treat seasonal depression as well as smoking cessation?

Back 36

Bupropion.

Front 37

Over doses are common method of suicide with TCADs, what should be given to reverse the fatal arrhythmias?

Back 37

NaHCO3-.

**Over doses are also seen with MAOIs

Front 38

ALL Anti-depressants are BLACK BOXED for what?

Back 38

Inc risk of Suicidality in pts < 25 y/o

Front 39

Which Anti-depressant is Category D? why?

Back 39

Paroxetine: Inc risk for cardiac septal defects in the first trimester

Front 40

when is permanent maintainence therapy suggested for depressed pts?

Back 40

when patient has 2+ serious major depressive episodes in the last 5 years or 3+ in a lifetime

Front 41

Tx for Premenstrual Dysphoric Disorder

Back 41

1.Flouxetine.

2.Sertraline

Front 42

Which SSRI is also useful in Tx of BULEMIA

Back 42

Fluoxetine

Front 43

Which Anti-depressant is used in treating obesity

Back 43

Bupropion

Front 44

What Anti-depressant can be used to treat hot flashes (Vasomotor symptoms in menopause)?

Back 44

Desvenlafaxine

Front 45

St. John Wort is used to treat depression, however, you should be worried about what?

Back 45

it can cause drug drug interactions b/c it induces CYP3A4

Front 46

Tx for Bipolar

Back 46

1.Manic Phase: Lithium, Valproate, Carbamazepine.

2.Bipolar depression: Atypical anti-psychotic

Front 47

What drugs can BLOCK the renal clearance of Lithium?

Back 47

1.Thiazide Diuretics.

2.NSAIDS

Front 48

Lithium has a narrow therapeutic window, what main SE should you be worried about? what would you tx it with?

Back 48

Nephrogenic Diabetes Insipidus (polyuria, Polydipsia).

**treat with amiloride

Front 49

What nerve growth factor is critical in the regulation of neural plasticity, resilience, and neurogenesis?

Back 49

brain-derived neurotrophic factor (BDNF)

evidence points to depression may be due to loss of neurotrophic support

Front 50

What's some other key things about BDNF?

Back 50

Stress and pain are associated in a drop in BDNF levels
-this leads to specific areas of atrophic structural changes, specifically the hippocampus, medial frontal cortex, and anterior cingulate

Chronic activation of Monoamine receptors increase BDNF transcription

Front 51

What's some other neuroendocrine factors with depression?

Back 51

abnormalities in the HPA Axis
elevated cortisol levels
non-suppression of ACTH with dexamethasone test
Chronically elevate CRH
25% have thyroid dysregulation

Front 52

Tell me about SSRI's

Back 52

Primary action is the inhibition of the serotonin transporter (SERT).

Most commonly used, with *Fluoxetine* as the prototype

Front 53

How do SSRI's inhibit the SERT?

Back 53

Causes an allosteric conformational change in the transporter, so technically not blocking it.

At therapeutic doses, only about 80% of the transporters activity is inhibited

Front 54

Which SSRI's are potent CYP2D6 inhibitors?

Back 54

Paroxetine and Fluoxetine

Front 55

Which SSRI is a potent CYP3A4 inhibitor?

Back 55

Fluvoxamine

Front 56

What should be the concern about giving SSRI's and MAOI's together?

Back 56

Serotonin Syndrome

Front 57

Tell me about SNRI's

Back 57

bind both SERT and Norepinephrine transporter (NET)

**MAJOR USE IN PAIN DISORDERS, like fibromyalgia and neuropathies**-----> Milnacipran for fibromyalgia

Front 58

SNRI Pharmacodynamics

Back 58

Velnlafaxine is a weak inhibitor of NET

Deslvenlafaxine, Duloxetine, and milnaciprain are balanced inhibitors of SERT and NET

SNRI's have a greater affinity for SERT than NET

Front 59

What are the adverse noradrenergic FX of SNRI's?

Back 59

increased BP, HR, and CNS activation (insomnia, anxiety, agitation)

also has a discontinuation syndrome

Front 60

Which of the SNRI/SSRI's has the most cardiac toxicity?

Back 60

Venlafaxine

Front 61

Tell me about Tricyclic Antidepressant/TCA's/TCAD's

Back 61

was originally the primary class of antidepressants until SSRI's were introduced. They treat depression unresponsive to SSRI's, SNRI's, pain conditions, enuresis, and insomnia.

Loss of popularity due to poor tolerability, difficult to use, and lethal OD's

Front 62

Which TCA has serotonin effects?

Back 62

Imipramine

Front 63

TCA's and receptor FX (know the red)

Back 63

Front 64

TCA Pharmacodynamics (know the red)

Back 64

Front 65

TCA's most concerning AFx?

Back 65

Potent antimuscarinic FX, with dry mouth, constipation, etc. (anti-DUMBBELS)

More common with amitriptyline and imipramine

Front 66

Be aware that TCA levels are elevated when other drugs inhibit CYP2D6 and can also have additive FX with other drugs metabolized by CYP2D6

Back 66

...just know it.

Front 67

What are the two 5HT2 antagonists?

Back 67

Trazodone and nefazodone (no longer used)

Front 68

how do the 5HT2 antagonists work?

Back 68

blockade of the 5HT2a receptors, the same target for LSD and mescaline.

Front 69

Why is Nefazodone no longer prescribed?

Back 69

hepatotoxicity, leading to lethal hepatic failure.

Front 70

Drug Interactions of 5HT2 antagonists?

Back 70

Nefazodone inhibits CYP3A4, but trazodone is a CYP3A4 substrate (inhibitors increase it's concentration

Front 71

Tell me about MAOI's

Back 71

target the A and B receptors non-selectively. Some structurally resemble amphetamines, and cause a CNS stimulation.

They are classified by specificity to A or B, and whether they are irreversible or reversible

Front 72

What's the main MAOI to know that is irreversible AND Non-selective?

Back 72

Phenelzine

Front 73

What's the difference between MAO receptor A vs B?

Back 73

A is in dopamine and NE neurons, and are found in the brain, gut, placenta, and liver.

B is in serotonin and histamine neurons, in the brain, liver, and platelets.

Both metabolize tryptamine and dopamine

Front 74

What are some AFx of MAOI's?

Back 74

Most common is orthostatic hypotension and weight gain

Blocks metabolism of tyramine

Sudden discontinuation causes delirium

Front 75

What's important SFx of Phenelzine?

Back 75

High rate of sexual FX (anorgasmia)
More sedation
Confusion at higher doses

Front 76

What's the triad of Serotonin Syndrome FX with MAOI's?

Back 76

cognitive, autonomic, and somatic FX

or the 3C's-> coma, cardiac, and clonus

Front 77

be aware that most serotonergic antidepressants need to be D/c'd for at least 2 wks prior to starting an MAOI

Back 77

know it.

Front 78

What are the drug choices for the following clinical situations:

Pain

Treatment of OCD

Smoking

Back 78

Pain-----> TCA's and SNRI's

Treatment of OCD------> SSRI's and clomipramine

Smoking------> bupropion and nortriptyline

Front 79

What drug class often used for suicidal overdose?

Back 79

TCA's---> cause fatal arrhythmias, BP changes, and anticholinergic FX

Antidote is Sodium Bicarb

Front 80

What's the hangup on giving antidepressants to patients under 25?

Back 80

Increased risk of suicidality

Front 81

What pregnancy categories are the antidepressants?

Back 81

Most are Category C, but Paroxetine causes cardiac septal defects-------> Category D

Front 82

What is Premenstrual Dysphoric Disorder, and how is it treated?

Back 82

During the late luteal phase of every cycle, with anxiety, depressed mood, irritability, insomnia, and fatigue

Treat with fluoxetine and sertraline

Front 83

What does St. John's Wort induce?

Back 83

CYP3A4-> lots of drug interactions

Front 84

Review the Bipolar slides at the end of the Affective Disorders lecture (~ slide 70 and on)

Adverse SFx of Lithium?

Back 84

Thyroid fxn decreased
nephrogenic Diabetes Insipidus
edema
CI'd in sick-sinus syndrome

TOXIC in pregnancy----> Ebstein's Anomaly (lethargic, cyanosis, poor suck and Moro reflexes, hepatomegaly)